Delivery of physiologically active compounds through an inhalation route

ABSTRACT

The present invention relates to the delivery of physiologically active compounds through an inhalation route. Specifically, it relates to aerosols containing physiologically active compounds that are used in inhalation therapy. In a method aspect of the present invention, the physiologically active compound is delivered to a patient through an inhalation route. The method comprises: a) heating a coating of a physiologically active compound, on a solid support, to form a vapor; and, b) passing air through the heated vapor to produce aerosol particles having less than 5% physiologically active compound degradation products. In a kit aspect of the present invention, a kit for delivering a physiologically active compound through an inhalation route is provided which comprises: a) a thin coating of a physiologically active compound, and b) a device for dispensing said thin coating as a condensation aerosol.

[0001] This application is a continuation of U.S. patent applicationSer. No. 10/154,765 entitled “Delivery of Physiologically ActiveCompounds Through an Inhalation Route,” filed May 23, 2002, Rabinowitzand Zaffaroni, which priority to U.S. provisional application Serial No.60/294,203 entitled “Thermal Vapor Delivery of Drugs,” filed May 24,2001, Rabinowitz and Zaffaroni and U.S. provisional application SerialNo. 60/317,479 entitled “Aerosol Drug Delivery,” filed Sep. 5, 2001,Rabinowitz and Zaffaroni, the entire disclosures of which are herebyincorporated by reference.

FIELD OF THE INVENTION

[0002] The present invention relates to the delivery of physiologicallyactive compounds through an inhalation route. Specifically, it relatesto aerosols containing physiologically active compounds that are used ininhalation therapy.

BACKGROUND OF THE INVENTION

[0003] It is desirable to provide a new route of administration forphysiologically active compounds that rapidly produce peak plasmaconcentrations of the compound. The provision of such a route is anobject of the present invention.

SUMMARY OF THE INVENTION

[0004] The present invention relates to the delivery of physiologicallyactive compounds through an inhalation route. Specifically, it relatesto aerosols containing physiologically active compounds that are used ininhalation therapy.

[0005] In a composition aspect of the present invention, the aerosolcomprises particles comprising at least 5 percent by weight ofchlordiazepoxide, betahistine, clonidine, testosterone, conjugatedestrogens, estrogen esters, estradiol, estradiol esters, ethinylestradiol, ethinyl estradiol esters, or hyoscyamine. Preferably, theparticles comprise at least 10 percent by weight of chlordiazepoxide,betahistine, clonidine, testosterone, conjugated estrogens, estrogenesters, estradiol, estradiol esters, ethinyl estradiol, ethinylestradiol esters, or hyoscyamine. More preferably, the particlescomprise at least 20 percent, 30 percent, 40 percent, 50 percent, 60percent, 70 percent, 80 percent, 90 percent, 95 percent, 97 percent, 99percent, 99.5 percent or 99.97 percent by weight of chlordiazepoxide,betahistine, clonidine, testosterone, conjugated estrogens, estrogenesters, estradiol, estradiol esters, ethinyl estradiol, ethinylestradiol esters, or hyoscyamine.

[0006] Typically, the aerosol has a mass of at least 1 μg. Preferably,the aerosol has a mass of at least 10 μg. More preferably, the aerosolhas a mass of at least 20 μg.

[0007] Typically, the aerosol particles comprise less than 10 percent byweight of chlordiazepoxide, betahistine, clonidine, testosterone,conjugated estrogens, estrogen esters, estradiol, estradiol esters,ethinyl estradiol, ethinyl estradiol esters, or hyoscyamine degradationproducts. Preferably, the particles comprise less than 5 percent byweight of chlordiazepoxide, betahistine, clonidine, testosterone,conjugated estrogens, estrogen esters, estradiol, estradiol esters,ethinyl estradiol, ethinyl estradiol esters, or hyoscyamine degradationproducts. More preferably, the particles comprise less than 2.5, 1, 0.5,0.1 or 0.03 percent by weight of chlordiazepoxide, betahistine,clonidine, testosterone, conjugated estrogens, estrogen esters,estradiol, estradiol esters, ethinyl estradiol, ethinyl estradiolesters, or hyoscyamine degradation products.

[0008] Typically, the aerosol particles comprise less than 90 percent byweight of water. Preferably, the particles comprise less than 80 percentby weight of water. More preferably, the particles comprise less than 70percent, 60 percent, 50 percent, 40 percent, 30 percent, 20 percent, 10percent, or 5 percent by weight of water.

[0009] Typically, at least 50 percent by weight of the aerosol isamorphous in form, wherein crystalline forms make up less than 50percent by weight of the total aerosol weight, regardless of the natureof individual particles. Preferably, at least 75 percent by weight ofthe aerosol is amorphous in form. More preferably, at least 90 percentby weight of the aerosol is amorphous in form.

[0010] Typically, where the aerosol comprises chlordiazepoxide, theaerosol has an inhalable aerosol drug mass density of between 1 mg/L and40 mg/L. Preferably, the aerosol has an inhalable aerosol drug massdensity of between 2 mg/L and 30 mg/L. More preferably, the aerosol hasan inhalable aerosol drug mass density of between 3 mg/L and 20 mg/L.

[0011] Typically, where the aerosol comprises betahistine, the aerosolhas an inhalable aerosol drug mass density of between 0.5 mg/L and 50mg/L. Preferably, the aerosol has an inhalable aerosol drug mass densityof between 2 mg/L and 30 mg/L. More preferably, the aerosol has aninhalable aerosol drug mass density of between 5 mg/L and 20 mg/L.

[0012] Typically, where the aerosol comprises clonidine, the aerosol hasan inhalable aerosol drug mass density of between 0.02 mg/L and 2 mg/L.Preferably, the aerosol has an inhalable aerosol drug mass density ofbetween 0.03 mg/L and 1.5 mg/L. More preferably, the aerosol has aninhalable aerosol drug mass density of between 0.05 mg/L and 1 mg/L.

[0013] Typically, where the aerosol comprises testosterone, the aerosolhas an inhalable aerosol drug mass density of between 0.1 mg/L and 20mg/L. Preferably, the aerosol has an inhalable aerosol drug mass densityof between 0.2 mg/L and 10 mg/L. More preferably, the aerosol has aninhalable aerosol drug mass density of between 0.5 mg/L and 5 mg/L.

[0014] Typically, where the aerosol comprises conjugated estrogens orestrogen esters, the aerosol has an inhalable aerosol drug mass densityof between 0.05 mg/L and 5 mg/L. Preferably, the aerosol has aninhalable aerosol drug mass density of between 0.1 mg/L and 2 mg/L. Morepreferably, the aerosol has an inhalable aerosol drug mass density ofbetween 0.15 mg/L and 1.5 mg/L.

[0015] Typically, where the aerosol comprises conjugated estradiol,estradiol esters, ethinyl estradiol, or ethinyl estradiol esters, theaerosol has an inhalable aerosol drug mass density of between 0.001 mg/Land 0.2 mg/L. Preferably, the aerosol has an inhalable aerosol drug massdensity of between 0.002 mg/L and 0.1 mg/L. More preferably, the aerosolhas an inhalable aerosol drug mass density of between 0.004 mg/L and0.05 mg/L.

[0016] Typically, where the aerosol comprises hyoscyamine, the aerosolhas an inhalable aerosol drug mass density of between 0.01 mg/L and 1mg/L. Preferably, the aerosol has an inhalable aerosol drug mass densityof between 0.025 mg/L and 0.75 mg/L. More preferably, the aerosol has aninhalable aerosol drug mass density of between 0.05 mg/L and 0.5 mg/L.

[0017] Typically, the aerosol has an inhalable aerosol particle densitygreater than 10⁶ particles/mL. Preferably, the aerosol has an inhalableaerosol particle density greater than 10⁷ particles/mL. More preferably,the aerosol has an inhalable aerosol particle density greater than 10⁸particles/mL.

[0018] Typically, the aerosol particles have a mass median aerodynamicdiameter of less than 5 microns. Preferably, the particles have a massmedian aerodynamic diameter of less than 3 microns. More preferably, theparticles have a mass median aerodynamic diameter of less than 2 or 1micron(s).

[0019] Typically, the geometric standard deviation around the massmedian aerodynamic diameter of the aerosol particles is less than 3.0.Preferably, the geometric standard deviation is less than 2.85. Morepreferably, the geometric standard deviation is less than 2.7.

[0020] Typically, the aerosol is formed by heating a compositioncontaining chlordiazepoxide, betahistine, clonidine, testosterone,conjugated estrogens, estrogen esters, estradiol, estradiol esters,ethinyl estradiol, ethinyl estradiol esters, or hyoscyamine to form avapor and subsequently allowing the vapor to condense into an aerosol.

[0021] In a method aspect of the present invention, chlordiazepoxide,betahistine, clonidine, testosterone, conjugated estrogens, estrogenesters, estradiol, estradiol esters, ethinyl estradiol, ethinylestradiol esters, or hyoscyamine is delivered to a mammal through aninhalation route. The method comprises: a) heating a composition,wherein the composition comprises at least 5 percent by weight ofchlordiazepoxide, betahistine, clonidine, testosterone, conjugatedestrogens, estrogen esters, estradiol, estradiol esters, ethinylestradiol, ethinyl estradiol esters, or hyoscyamine; and, b) allowingthe vapor to cool, thereby forming a condensation aerosol comprisingparticles, which is inhaled by the mammal. Preferably, the compositionthat is heated comprises at least 10 percent by weight ofchlordiazepoxide, betahistine, clonidine, testosterone, conjugatedestrogens, estrogen esters, estradiol, estradiol esters, ethinylestradiol, ethinyl estradiol esters, or hyoscyamine. More preferably,the composition comprises 20 percent, 30 percent, 40 percent, 50percent, 60 percent, 70 percent, 80 percent, 90 percent, 95 percent, 97percent, 99 percent, 99.5 percent, 99.9 percent or 99.97 percent byweight of chlordiazepoxide, betahistine, clonidine, testosterone,conjugated estrogens, estrogen esters, estradiol, estradiol esters,ethinyl estradiol, ethinyl estradiol esters, or hyoscyamine.

[0022] Typically, the delivered aerosol particles comprise at least 5percent by weight of chlordiazepoxide, betahistine, clonidine,testosterone, conjugated estrogens, estrogen esters, estradiol,estradiol esters, ethinyl estradiol, ethinyl estradiol esters, orhyoscyamine. Preferably, the particles comprise at least 10 percent byweight of chlordiazepoxide, betahistine, clonidine, testosterone,conjugated estrogens, estrogen esters, estradiol, estradiol esters,ethinyl estradiol, ethinyl estradiol esters, or hyoscyamine. Morepreferably, the particles comprise at least 20 percent, 30 percent, 40percent, 50 percent, 60 percent, 70 percent, 80 percent, 90 percent, 95percent, 97 percent, 99 percent, 99.5 percent, 99.9 percent or 99.97percent by weight of chlordiazepoxide, betahistine, clonidine,testosterone, conjugated estrogens, estrogen esters, estradiol,estradiol esters, ethinyl estradiol, ethinyl estradiol esters, orhyoscyamine.

[0023] Typically, the delivered aerosol has a mass of at least 1 μg.Preferably, the aerosol has a mass of at least 10 μg. More preferably,the aerosol has a mass of at least 20 μg.

[0024] Typically, the delivered aerosol particles comprise less than 10percent by weight of chlordiazepoxide, betahistine, clonidine,testosterone, conjugated estrogens, estrogen esters, estradiol,estradiol esters, ethinyl estradiol, ethinyl estradiol esters, orhyoscyamine degradation products. Preferably, the particles compriseless than 5 percent by weight of chlordiazepoxide, betahistine,clonidine, testosterone, conjugated estrogens, estrogen esters,estradiol, estradiol esters, ethinyl estradiol, ethinyl estradiolesters, or hyoscyamine degradation products. More preferably, theparticles comprise less than 2.5, 1, 0.5, 0.1 or 0.03 percent by weightof chlordiazepoxide, betahistine, clonidine, testosterone, conjugatedestrogens, estrogen esters, estradiol, estradiol esters, ethinylestradiol, ethinyl estradiol esters, or hyoscyamine degradationproducts.

[0025] Typically, the particles of the delivered condensation aerosolhave a mass median aerodynamic diameter of less than 5 microns.Preferably, the particles have a mass median aerodynamic diameter ofless than 3 microns. More preferably, the particles have a mass medianaerodynamic diameter of less than 2 or 1 micron(s).

[0026] Typically, the geometric standard deviation around the massmedian aerodynamic diameter of the aerosol particles is less than 3.0.Preferably, the geometric standard deviation is less than 2.85. Morepreferably, the geometric standard deviation is less than 2.7.

[0027] Typically, the particles of the delivered condensation aerosolcomprise less than 90 percent by weight of water. Preferably, theparticles comprise less than 80 percent by weight of water. Morepreferably, the particles comprise less than 70 percent, 60 percent, 50percent, 40 percent, 30 percent, 20 percent, 10 percent, or 5 percent byweight of water.

[0028] Typically, at least 50 percent by weight of the aerosol isamorphous in form, wherein crystalline forms make up less than 50percent by weight of the total aerosol weight, regardless of the natureof individual particles. Preferably, at least 75 percent by weight ofthe aerosol is amorphous in form. More preferably, at least 90 percentby weight of the aerosol is amorphous in form.

[0029] Typically, where the aerosol comprises chlordiazepoxide, thedelivered aerosol has an inhalable aerosol drug mass density of between1 mg/L and 40 mg/L. Preferably, the delivered aerosol has an inhalableaerosol drug mass density of between 2 mg/L and 30 mg/L. Morepreferably, the delivered aerosol has an inhalable aerosol drug massdensity of between 3 mg/L and 20 mg/L.

[0030] Typically, where the aerosol comprises betahistine, the deliveredaerosol has an inhalable aerosol drug mass density of between 0.5 mg/Land 50 mg/L. Preferably, the delivered aerosol has an inhalable aerosoldrug mass density of between 2 mg/L and 30 mg/L. More preferably, thedelivered aerosol has an inhalable aerosol drug mass density of between5 mg/L and 20 mg/L.

[0031] Typically, where the delivered aerosol comprises clonidine, theaerosol has an inhalable aerosol drug mass density of between 0.02 mg/Land 2 mg/L. Preferably, the delivered aerosol has an inhalable aerosoldrug mass density of between 0.03 mg/L and 1.5 mg/L. More preferably,the delivered aerosol has an inhalable aerosol drug mass density ofbetween 0.05 mg/L and 1 mg/L.

[0032] Typically, where the aerosol comprises testosterone, thedelivered aerosol has an inhalable aerosol drug mass density of between0.1 mg/L and 20 mg/L. Preferably, the delivered aerosol has an inhalableaerosol drug mass density of between 0.2 mg/L and 10 mg/L. Morepreferably, the delivered aerosol has an inhalable aerosol drug massdensity of between 0.5 mg/L and 5 mg/L.

[0033] Typically, where the aerosol comprises conjugated estrogens orestrogen esters, the delivered aerosol has an inhalable aerosol drugmass density of between 0.05 mg/L and 5 mg/L. Preferably, the deliveredaerosol has an inhalable aerosol drug mass density of between 0.1 mg/Land 2 mg/L. More preferably, the delivered aerosol has an inhalableaerosol drug mass density of between 0.15 mg/L and 1.5 mg/L.

[0034] Typically, where the aerosol comprises conjugated estradiol,estradiol esters, ethinyl estradiol, or ethinyl estradiol esters, thedelivered aerosol has an inhalable aerosol drug mass density of between0.001 mg/L and 0.2 mg/L. Preferably, the delivered aerosol has aninhalable aerosol drug mass density of between 0.002 mg/L and 0.1 mg/L.More preferably, the delivered aerosol has an inhalable aerosol drugmass density of between 0.004 mg/L and 0.05 mg/L.

[0035] Typically, where the aerosol comprises hyoscyamine, the deliveredaerosol has an inhalable aerosol drug mass density of between 0.01 mg/Land 1 mg/L. Preferably, the delivered aerosol has an inhalable aerosoldrug mass density of between 0.025 mg/L and 0.75 mg/L. More preferably,the delivered aerosol has an inhalable aerosol drug mass density ofbetween 0.05 mg/L and 0.5 mg/L.

[0036] Typically, the delivered aerosol has an inhalable aerosolparticle density greater than 10⁶ particles/mL. Preferably, the aerosolhas an inhalable aerosol particle density greater than 10⁷ particles/mL.More preferably, the aerosol has an inhalable aerosol particle densitygreater than 10⁸ particles/mL.

[0037] Typically, the rate of inhalable aerosol particle formation ofthe delivered condensation aerosol is greater than 10⁸ particles persecond. Preferably, the aerosol is formed at a rate greater than 10⁹inhalable particles per second. More preferably, the aerosol is formedat a rate greater than 10¹⁰ inhalable particles per second.

[0038] Typically, the delivered aerosol is formed at a rate greater than0.25 mg/second. Preferably, the aerosol is formed at a rate greater than0.5 mg/second. More preferably, the aerosol is formed at a rate greaterthan 1 or 2 mg/second.

[0039] Typically, where the aerosol comprises chlordiazepoxide, between1 mg and 40 mg of chlordiazepoxide is delivered to the mammal in asingle inspiration. Preferably, between 2 mg and 30 mg ofchlordiazepoxide is delivered to the mammal in a single inspiration.More preferably, between 3 mg and 20 mg of chlordiazepoxide is deliveredto the mammal in a single inspiration.

[0040] Typically, where the aerosol comprises betahistine, between 0.5mg and 50 mg of betahistine is delivered to the mammal in a singleinspiration. Preferably, between 2 mg and 30 mg of betahistine isdelivered to the mammal in a single inspiration. More preferably,between 5 mg and 20 mg of betahistine is delivered to the mammal in asingle inspiration.

[0041] Typically, where the aerosol comprises clonidine, between 0.02 mgand 2 mg of clonidine is delivered to the mammal in a singleinspiration. Preferably, between 0.03 mg and 1.5 mg of clonidine isdelivered to the mammal in a single inspiration. More preferably,between 0.05 mg and 1 mg of clonidine is delivered to the mammal in asingle inspiration.

[0042] Typically, where the aerosol comprises testosterone, between 0.1mg and 20 mg of testosterone is delivered to the mammal in a singleinspiration. Preferably, between 0.2 mg and 10 mg of testosterone isdelivered to the mammal in a single inspiration. More preferably,between 0.5 mg and 5 mg of testosterone is delivered to the mammal in asingle inspiration.

[0043] Typically, where the aerosol comprises conjugated estrogens orestrogen esters, between 0.05 mg and 5 mg of conjugated estrogens orestrogen esters is delivered to the mammal in a single inspiration.Preferably, between 0.1 mg and 2 mg of conjugated estrogens or estrogenesters is delivered to the mammal in a single inspiration. Morepreferably, between 0.15 mg and 1.5 mg of conjugated estrogens orestrogen esters is delivered to the mammal in a single inspiration.

[0044] Typically, where the aerosol comprises conjugated estradiol,estradiol esters, ethinyl estradiol, or ethinyl estradiol esters,between 0.001 mg and 0.2 mg of conjugated conjugated estradiol,estradiol esters, ethinyl estradiol, or ethinyl estradiol esters isdelivered to the mammal in a single inspiration. Preferably, between0.002 mg and 0.1 mg of conjugated estradiol, estradiol esters, ethinylestradiol, or ethinyl estradiol esters is delivered to the mammal in asingle inspiration. More preferably, between 0.004 mg and 0.05 mg ofconjugated estradiol, estradiol esters, ethinyl estradiol, or ethinylestradiol esters is delivered to the mammal in a single inspiration.

[0045] Typically, where the aerosol comprises hyoscyamine, between 0.01mg and 1 mg of hyoscyamine is delivered to the mammal in a singleinspiration. Preferably, between 0.025 mg and 0.75 mg of hyoscyamine isdelivered to the mammal in a single inspiration. More preferably,between 0.05 mg and 0.5 mg of hyoscyamine is delivered to the mammal ina single inspiration.

[0046] Typically, the delivered condensation aerosol results in a peakplasma concentration of chlordiazepoxide, betahistine, clonidine,testosterone, conjugated estrogens, estrogen esters, estradiol,estradiol esters, ethinyl estradiol, ethinyl estradiol esters, orhyoscyamine in the mammal in less than 1 h. Preferably, the peak plasmaconcentration is reached in less than 0.5 h. More preferably, the peakplasma concentration is reached in less than 0.2, 0.1, 0.05, 0.02, 0.01,or 0.005 h (arterial measurement).

[0047] In a kit aspect of the present invention, a kit for deliveringchlordiazepoxide, betahistine, clonidine, testosterone, conjugatedestrogens, estrogen esters, estradiol, estradiol esters, ethinylestradiol, ethinyl estradiol esters, or hyoscyamine through aninhalation route to a mammal is provided which comprises: a) acomposition comprising at least 5 percent by weight of chlordiazepoxide,betahistine, clonidine, testosterone, conjugated estrogens, estrogenesters, estradiol, estradiol esters, ethinyl estradiol, ethinylestradiol esters, or hyoscyamine; and, b) a device that forms achlordiazepoxide, betahistine, clonidine, testosterone, conjugatedestrogens, estrogen esters, estradiol, estradiol esters, ethinylestradiol, ethinyl estradiol esters, or hyoscyamine containing aerosolfrom the composition, for inhalation by the mammal. Preferably, thecomposition comprises at least 10 percent by weight of chlordiazepoxide,betahistine, clonidine, testosterone, conjugated estrogens, estrogenesters, estradiol, estradiol esters, ethinyl estradiol, ethinylestradiol esters, or hyoscyamine. More preferably, the compositioncomprises at least 20 percent, 30 percent, 40 percent, 50 percent, 60percent, 70 percent, 80 percent, 90 percent, 95 percent, 97 percent, 99percent, 99.5 percent, 99.9 percent or 99.97 percent by weight ofchlordiazepoxide, betahistine, clonidine, testosterone, conjugatedestrogens, estrogen esters, estradiol, estradiol esters, ethinylestradiol, ethinyl estradiol esters, or hyoscyamine.

[0048] Typically, the device contained in the kit comprises: a) anelement for heating the chlordiazepoxide, betahistine, clonidine,testosterone, conjugated estrogens, estrogen esters, estradiol,estradiol esters, ethinyl estradiol, ethinyl estradiol esters, orhyoscyamine composition to form a vapor; b) an element allowing thevapor to cool to form an aerosol; and, c) an element permitting themammal to inhale the aerosol.

BRIEF DESCRIPTION OF THE FIGURE

[0049]FIG. 1 shows a device used to deliver chlordiazepoxide,betahistine, clonidine, testosterone, conjugated estrogens, estrogenesters, estradiol, estradiol esters, ethinyl estradiol, ethinylestradiol esters, or hyoscyamine containing aerosols to a mammal throughan inhalation route.

DETAILED DESCRIPTION OF THE INVENTION

[0050] Definitions

[0051] “Aerodynamic diameter” of a given particle refers to the diameterof a spherical droplet with a density of 1 g/mL (the density of water)that has the same settling velocity as the given particle.

[0052] “Aerosol” refers to a suspension of solid or liquid particles ina gas.

[0053] “Aerosol drug mass density” refers to the mass ofchlordiazepoxide, betahistine, clonidine, testosterone, conjugatedestrogens, estrogen esters, estradiol, estradiol esters, ethinylestradiol, ethinyl estradiol esters, or hyoscyamine per unit volume ofaerosol.

[0054] “Aerosol mass density” refers to the mass of particulate matterper unit volume of aerosol.

[0055] “Aerosol particle density” refers to the number of particles perunit volume of aerosol.

[0056] “Amorphous particle” refers to a particle that does not containmore than 50 percent by weight of a crystalline form. Preferably, theparticle does not contain more than 25 percent by weight of acrystalline form. More preferably, the particle does not contain morethan 10 percent by weight of a crystalline form.

[0057] “Betahistine” refers to N-methyl-2-pyridineethanamine.

[0058] “Betahistine degradation product” refers to a compound resultingfrom a chemical modification of betahistine. The modification, forexample, can be the result of a thermally or photochemically inducedreaction. Such reactions include, without limitation, oxidation andhydrolysis.

[0059] “Chlordiazepoxide” refers to7-chloro-N-methyl-5-phenyl-3H-1,4-benzodiazepin-2-amine-4-oxide.

[0060] “Chlordiazepoxide degradation product” refers to a compoundresulting from a chemical modification of chlordiazepoxide. Themodification, for example, can be the result of a thermally orphotochemically induced reaction. Such reactions include, withoutlimitation, oxidation and hydrolysis.

[0061] “Clonidine” refers to2,6-dichloro-N-2-imidazolidinylidene-benzeneamine.

[0062] “Clonidine degradation product” refers to a compound resultingfrom a chemical modification of clonidine. The modification, forexample, can be the result of a thermally or photochemically inducedreaction. Such reactions include, without limitation, oxidation andhydrolysis.

[0063] “Condensation aerosol” refers to an aerosol formed byvaporization of a substance followed by condensation of the substanceinto an aerosol.

[0064] “Conjugated estrogen” refers to estrogen sulfates. This includesa blend of estrogen sulfates containing estrone, equilin, and 17α-dihydroequilin.

[0065] “Conjugated estrogen degradation product” refers to a compoundresulting from a chemical modification of a conjugated estrogen. Themodification, for example, can be the result of a thermally orphotochemically induced reaction. Such reactions include, withoutlimitation, oxidation and hydrolysis.

[0066] “Estradiol” refers to estra-1,3,5(10)-triene-3,17-diol.

[0067] “Estradiol degradation product” refers to a compound resultingfrom a chemical modification of estradiol. The modification, forexample, can be the result of a thermally or photochemically inducedreaction. Such reactions include, without limitation, oxidation andhydrolysis.

[0068] “Estradiol ester” refers to an ester derived from theesterification of an alcohol moiety of estradiol.

[0069] “Estradiol ester degradation product” refers to a compoundresulting from a chemical modification of an estradiol ester. Themodification, for example, can be the result of a thermally orphotochemically induced reaction. Such reactions include, withoutlimitation, oxidation and hydrolysis.

[0070] “Estrogen ester” refers to an ester derived from theesterification of an alcohol moiety of estrogen.

[0071] “Estrogen ester degradation product” refers to a compoundresulting from a chemical modification of an estrogen ester. Themodification, for example, can be the result of a thermally orphotochemically induced reaction. Such reactions include, withoutlimitation, oxidation and hydrolysis.

[0072] “Ethinyl estradiol” refers to19-nor-17α-pregna-1,3,5(10)-trien-20-yne-3,17-diol.

[0073] “Ethinyl estradiol degradation product” refers to a compoundresulting from a chemical modification of ethinyl estradiol. Themodification, for example, can be the result of a thermally orphotochemically induced reaction. Such reactions include, withoutlimitation, oxidation and hydrolysis.

[0074] “Ethinyl estradiol ester” refers to an ester derived from theesterification of an alcohol moiety of ethinyl estradiol.

[0075] “Ethinyl estradiol ester degradation product” refers to acompound resulting from a chemical modification of an ethinyl estradiolester. The modification, for example, can be the result of a thermallyor photochemically induced reaction. Such reactions include, withoutlimitation, oxidation and hydrolysis.

[0076] “Hyoscyamine” refers to α-(hydroxymethyl)benzeneacetic acid8-methyl-8-azabicyclo[3.2.1]oct-3-yl ester.

[0077] “Hyoscyamine degradation product” refers to a compound resultingfrom a chemical modification of hyoscyamine. The modification, forexample, can be the result of a thermally or photochemically inducedreaction. Such reactions include, without limitation, oxidation andhydrolysis.

[0078] “Inhalable aerosol drug mass density” refers to the aerosol drugmass density produced by an inhalation device and delivered into atypical patient tidal volume.

[0079] “Inhalable aerosol mass density” refers to the aerosol massdensity produced by an inhalation device and delivered into a typicalpatient tidal volume.

[0080] “Inhalable aerosol particle density” refers to the aerosolparticle density of particles of size between 100 nm and 5 micronsproduced by an inhalation device and delivered into a typical patienttidal volume.

[0081] “Mass median aerodynamic diameter” or “MMAD” of an aerosol refersto the aerodynamic diameter for which half the particulate mass of theaerosol is contributed by particles with an aerodynamic diameter largerthan the MMAD and half by particles with an aerodynamic diameter smallerthan the MMAD.

[0082] “Rate of aerosol formation” refers to the mass of aerosolizedparticulate matter produced by an inhalation device per unit time.

[0083] “Rate of inhalable aerosol particle formation” refers to thenumber of particles of size between 100 nm and 5 microns produced by aninhalation device per unit time.

[0084] “Rate of drug aerosol formation” refers to the mass ofaerosolized chlordiazepoxide, betahistine, clonidine, testosterone,conjugated estrogens, estrogen esters, estradiol, estradiol esters,ethinyl estradiol, ethinyl estradiol esters, or hyoscyamine produced byan inhalation device per unit time.

[0085] “Settling velocity” refers to the terminal velocity of an aerosolparticle undergoing gravitational settling in air.

[0086] “Testosterone” refers to 17β-hydroxyandrost-4-en-3-one.

[0087] “Testosterone degradation product” refers to a compound resultingfrom a chemical modification of testosterone. The modification, forexample, can be the result of a thermally or photochemically inducedreaction. Such reactions include, without limitation, oxidation andhydrolysis.

[0088] “Typical patient tidal volume” refers to 1 L for an adult patientand 15 mL/kg for a pediatric patient.

[0089] “Vapor” refers to a gas, and “vapor phase” refers to a gas phase.The term “thermal vapor” refers to a vapor phase, aerosol, or mixture ofaerosol-vapor phases, formed preferably by heating.

[0090] Formation of Physiologically Active Compound Containing Aerosols

[0091] Any suitable method is used to form the aerosols of the presentinvention. A preferred method, however, involves heating a compositioncomprising chlordiazepoxide, betahistine, clonidine, testosterone,conjugated estrogens, estrogen esters, estradiol, estradiol esters,ethinyl estradiol, ethinyl estradiol esters, or hyoscyamine to form avapor, followed by cooling of the vapor such that it condenses toprovide an chlordiazepoxide, betahistine, clonidine, testosterone,conjugated estrogens, estrogen esters, estradiol, estradiol esters,ethinyl estradiol, ethinyl estradiol esters, or hyoscyamine comprisingaerosol (condensation aerosol). The composition is heated in one of fourforms: as pure active compound (i.e., pure chlordiazepoxide,betahistine, clonidine, testosterone, conjugated estrogens, estrogenesters, estradiol, estradiol esters, ethinyl estradiol, ethinylestradiol esters, or hyoscyamine) as a mixture of active compound and apharmaceutically acceptable excipient; as a salt form of the pure activecompound; and, as a mixture of active compound salt form and apharmaceutically acceptable excipient.

[0092] Salt forms of chlordiazepoxide, betahistine, clonidine,testosterone, conjugated estrogens, estrogen esters, estradiol,estradiol esters, ethinyl estradiol, ethinyl estradiol esters, orhyoscyamine are either commercially available or are obtained from thecorresponding free base using well known methods in the art. A varietyof pharmaceutically acceptable salts are suitable for aerosolization.Such salts include, without limitation, the following: hydrochloricacid, hydrobromic acid, acetic acid, maleic acid, formic acid, andfumaric acid salts.

[0093] Pharmaceutically acceptable excipients may be volatile ornonvolatile. Volatile excipients, when heated, are concurrentlyvolatilized, aerosolized and inhaled with the antihistamine. Classes ofsuch excipients are known in the art and include, without limitation,gaseous, supercritical fluid, liquid and solid solvents. The followingis a list of exemplary carriers within the classes: water; terpenes,such as menthol; alcohols, such as ethanol, propylene glycol, glyceroland other similar alcohols; dimethylformamide; dimethylacetamide; wax;supercritical carbon dioxide; dry ice; and mixtures thereof.

[0094] Solid supports on which the composition is heated are of avariety of shapes. Examples of such shapes include, without limitation,cylinders of less than 1.0 mm in diameter, boxes of less than 1.0 mmthickness and virtually any shape permeated by small (e.g., less than1.0 mm-sized) pores. Preferably, solid supports provide a large surfaceto volume ratio (e.g., greater than 100 per meter) and a large surfaceto mass ratio (e.g., greater than 1 cm² per gram).

[0095] A solid support of one shape can also be transformed into anothershape with different properties. For example, a flat sheet of 0.25 mmthickness has a surface to volume ratio of approximately 8,000 permeter. Rolling the sheet into a hollow cylinder of 1 cm diameterproduces a support that retains the high surface to mass ratio of theoriginal sheet but has a lower surface to volume ratio (about 400 permeter).

[0096] A number of different materials are used to construct the solidsupports. Classes of such materials include, without limitation, metals,inorganic materials, carbonaceous materials and polymers. The followingare examples of the material classes: aluminum, silver, gold, stainlesssteel, copper and tungsten; silica, glass, silicon and alumina;graphite, porous carbons, carbon yams and carbon felts;polytetrafluoroethylene and polyethylene glycol. Combinations ofmaterials and coated variants of materials are used as well.

[0097] Where aluminum is used as a solid support, aluminum foil is asuitable material. Examples of silica, alumina and silicon basedmaterials include amphorous silica S-5631 (Sigma, St. Louis, Mo.),BCR171 (an alumina of defined surface area greater than 2 m²/g fromAldrich, St. Louis, Mo.) and a silicon wafer as used in thesemiconductor industry. Carbon yams and felts are available fromAmerican Kynol, Inc., New York, N.Y. Chromatography resins such asoctadecycl silane chemically bonded to porous silica are exemplarycoated variants of silica.

[0098] The heating of the chlordiazepoxide, betahistine, clonidine,testosterone, conjugated estrogens, estrogen esters, estradiol,estradiol esters, ethinyl estradiol, ethinyl estradiol esters, orhyoscyamine compositions is performed using any suitable method.Examples of methods by which heat can be generated include thefollowing: passage of current through an electrical resistance element;absorption of electromagnetic radiation, such as microwave or laserlight; and, exothermic chemical reactions, such as exothermic solvation,hydration of pyrophoric materials and oxidation of combustiblematerials.

[0099] Delivery of Physiologically Active Compound Containing Aerosols

[0100] Chlordiazepoxide, betahistine, clonidine, testosterone,conjugated estrogens, estrogen esters, estradiol, estradiol esters,ethinyl estradiol, ethinyl estradiol esters, or hyoscyamine containingaerosols of the present invention are delivered to a mammal using aninhalation device. Where the aerosol is a condensation aerosol, thedevice has at least three elements: an element for heating achlordiazepoxide, betahistine, clonidine, testosterone, conjugatedestrogens, estrogen esters, estradiol, estradiol esters, ethinylestradiol, ethinyl estradiol esters, or hyoscyamine containingcomposition to form a vapor; an element allowing the vapor to cool,thereby providing a condensation aerosol; and, an element permitting themammal to inhale the aerosol. Various suitable heating methods aredescribed above. The element that allows cooling is, in it simplestform, an inert passageway linking the heating means to the inhalationmeans. The element permitting inhalation is an aerosol exit portal thatforms a connection between the cooling element and the mammal'srespiratory system.

[0101] One device used to deliver a chlordiazepoxide, betahistine,clonidine, testosterone, conjugated estrogens, estrogen esters,estradiol, estradiol esters, ethinyl estradiol, ethinyl estradiolesters, or hyoscyamine containing aerosol is described in reference toFIG. 1. Delivery device 100 has a proximal end 102 and a distal end 104,a heating module 106, a power source 108, and a mouthpiece 110. Achlordiazepoxide, betahistine, clonidine, testosterone, conjugatedestrogens, estrogen esters, estradiol, estradiol esters, ethinylestradiol, ethinyl estradiol esters, or hyoscyamine composition isdeposited on a surface 112 of heating module 106. Upon activation of auser activated switch 114, power source 108 initiates heating of heatingmodule 106 (e.g, through ignition of combustible fuel or passage ofcurrent through a resistive heating element). The chlordiazepoxide,betahistine, clonidine, testosterone, conjugated estrogens, estrogenesters, estradiol, estradiol esters, ethinyl estradiol, ethinylestradiol esters, or hyoscyamine composition volatilizes due to theheating of heating module 106 and condenses to form a condensationaerosol prior to reaching the mouthpiece 1 10 at the proximal end of thedevice 102. Air flow traveling from the device distal end 104 to themouthpiece 110 carries the condensation aerosol to the mouthpiece 1 10,where it is inhaled by the mammal.

[0102] Devices, if desired, contain a variety of components tofacilitate the delivery of chlordiazepoxide, betahistine, clonidine,testosterone, conjugated estrogens, estrogen esters, estradiol,estradiol esters, ethinyl estradiol, ethinyl estradiol esters, orhyoscyamine containing aerosols. For instance, the device may includeany component known in the art to control the timing of drugaerosolization relative to inhalation (e.g., breath-actuation), toprovide feedback to patients on the rate and/or volume of inhalation, toprevent excessive use (i.e., “lock-out” feature), to prevent use byunauthorized individuals, and/or to record dosing histories.

[0103] Dosage of Physiologically Active Compound Containing Aerosols

[0104] The dosage amount of chlordiazepoxide, betahistine, clonidine,testosterone, conjugated estrogens, estrogen esters, estradiol,estradiol esters, ethinyl estradiol, ethinyl estradiol esters, orhyoscyamine in aerosol form is generally no greater than twice thestandard dose of the drug given orally. The following dosage amounts aretypical for the respective compounds: chlordiazepoxide, 10 mg;betahistine, 16 mg; clonidine, 0.1 mg; testosterone, 5 mg; conjugatedestrogens and estrogen esters, 0.625 mg; estradiol, estradiol esters,ethinyl estradiol and ethinyl estradiol esters, 0.02 mg; and,hyoscyamine, 0.15 mg. As aerosols, doses are generally provided asfollows for the same indications: chlordiazepoxide, 1 to 40 mg;betahistine, 0.5 to 50 mg; clonidine, 0.02 to 2 mg; testosterone, 0.1 to20 mg; conjugated estrogens and estrogen esters, 0.05 to 5 mg;estradiol, estradiol esters, ethinyl estradiol and ethinyl estradiolesters, 0.001 mg to 0.2 mg; and, hyoscyamine, 0.01 to 1 mg. A typicaldosage of a chlordiazepoxide, betahistine, clonidine, testosterone,conjugated estrogens, estrogen esters, estradiol, estradiol esters,ethinyl estradiol, ethinyl estradiol esters, or hyoscyamine aerosol iseither administered as a single inhalation or as a series of inhalationstaken within an hour or less (dosage equals sum of inhaled amounts).Where the drug is administered as a series of inhalations, a differentamount may be delivered in each inhalation.

[0105] One can determine the appropriate dose of a chlordiazepoxide,betahistine, clonidine, testosterone, conjugated estrogens, estrogenesters, estradiol, estradiol esters, ethinyl estradiol, ethinylestradiol esters, or hyoscyamine containing aerosol to treat aparticular condition using methods such as animal experiments and adose-finding (Phase I/II) clinical trial. One animal experiment involvesmeasuring plasma concentrations of drug in an animal after its exposureto the aerosol. Mammals such as dogs or primates are typically used insuch studies, since their respiratory systems are similar to that of ahuman. Initial dose levels for testing in humans is generally less thanor equal to the dose in the mammal model that resulted in plasma druglevels associated with a therapeutic effect in humans. Dose escalationin humans is then performed, until either an optimal therapeuticresponse is obtained or a dose-limiting toxicity is encountered.

[0106] Analysis of Physiologically Active Compound Containing Aerosols

[0107] Purity of a chlordiazepoxide, betahistine, clonidine,testosterone, conjugated estrogens, estrogen esters, estradiol,estradiol esters, ethinyl estradiol, ethinyl estradiol esters, orhyoscyamine containing aerosol is determined using a number of methods,examples of which are described in Sekine et al., Journal of ForensicScience 32:1271-1280 (1987) and Martin et al., Journal of AnalyticToxicology 13:158-162 (1989). One method involves forming the aerosol ina device through which a gas flow (e.g., air flow) is maintained,generally at a rate between 0.4 and 60 L/min. The gas flow carries theaerosol into one or more traps. After isolation from the trap, theaerosol is subjected to an analytical technique, such as gas or liquidchromatography, that permits a determination of composition purity.

[0108] A variety of different traps are used for aerosol collection. Thefollowing list contains examples of such traps: filters; glass wool;impingers; solvent traps, such as dry ice-cooled ethanol, methanol,acetone and dichloromethane traps at various pH values; syringes thatsample the aerosol; empty, low-pressure (e.g., vacuum) containers intowhich the aerosol is drawn; and, empty containers that fully surroundand enclose the aerosol generating device. Where a solid such as glasswool is used, it is typically extracted with a solvent such as ethanol.The solvent extract is subjected to analysis rather than the solid(i.e., glass wool) itself. Where a syringe or container is used, thecontainer is similarly extracted with a solvent.

[0109] The gas or liquid chromatograph discussed above contains adetection system (i.e., detector). Such detection systems are well knownin the art and include, for example, flame ionization, photon absorptionand mass spectrometry detectors. An advantage of a mass spectrometrydetector is that it can be used to determine the structure ofchlordiazepoxide, betahistine, clonidine, testosterone, conjugatedestrogens, estrogen esters, estradiol, estradiol esters, ethinylestradiol, ethinyl estradiol esters, or hyoscyamine degradationproducts.

[0110] Particle size distribution of a chlordiazepoxide, betahistine,clonidine, testosterone, conjugated estrogens, estrogen esters,estradiol, estradiol esters, ethinyl estradiol, ethinyl estradiolesters, or hyoscyamine containing aerosol is determined using anysuitable method in the art (e.g., cascade impaction). An Andersen EightStage Non-viable Cascade Impactor (Andersen Instruments, Smyrna, Ga.)linked to a furnace tube by a mock throat (USP throat, AndersenInstruments, Smyrna, Ga.) is one system used for cascade impactionstudies.

[0111] Inhalable aerosol mass density is determined, for example, bydelivering a drug-containing aerosol into a confined chamber via aninhalation device and measuring the mass collected in the chamber.Typically, the aerosol is drawn into the chamber by having a pressuregradient between the device and the chamber, wherein the chamber is atlower pressure than the device. The volume of the chamber shouldapproximate the tidal volume of an inhaling patient.

[0112] Inhalable aerosol drug mass density is determined, for example,by delivering a drug-containing aerosol into a confined chamber via aninhalation device and measuring the amount of active drug compoundcollected in the chamber. Typically, the aerosol is drawn into thechamber by having a pressure gradient between the device and thechamber, wherein the chamber is at lower pressure than the device. Thevolume of the chamber should approximate the tidal volume of an inhalingpatient. The amount of active drug compound collected in the chamber isdetermined by extracting the chamber, conducting chromatographicanalysis of the extract and comparing the results of the chromatographicanalysis to those of a standard containing known amounts of drug.

[0113] Inhalable aerosol particle density is determined, for example, bydelivering aerosol phase drug into a confined chamber via an inhalationdevice and measuring the number of particles of given size collected inthe chamber. The number of particles of a given size may be directlymeasured based on the light-scattering properties of the particles.Alternatively, the number of particles of a given size may be determinedby measuring the mass of particles within the given size range andcalculating the number of particles based on the mass as follows: Totalnumber of particles =Sum (from size range 1 to size range N) of numberof particles in each size range. Number of particles in a given sizerange=Mass in the size range/Mass of a typical particle in the sizerange. Mass of a typical particle in a given size range=π*D³φ/6, where Dis a typical particle diameter in the size range (generally, the meanboundary MMADs defining the size range) in microns, φ is the particledensity (in g/mL) and mass is given in units of picograms (g⁻¹²).

[0114] Rate of inhalable aerosol particle formation is determined, forexample, by delivering aerosol phase drug into a confined chamber via aninhalation device. The delivery is for a set period of time (e.g., 3 s),and the number of particles of a given size collected in the chamber isdetermined as outlined above. The rate of particle formation is equal tothe number of 100 nm to 5 micron particles collected divided by theduration of the collection time.

[0115] Rate of aerosol formation is determined, for example, bydelivering aerosol phase drug into a confined chamber via an inhalationdevice. The delivery is for a set period of time (e.g., 3 s), and themass of particulate matter collected is determined by weighing theconfined chamber before and after the delivery of the particulatematter. The rate of aerosol formation is equal to the increase in massin the chamber divided by the duration of the collection time.Alternatively, where a change in mass of the delivery device orcomponent thereof can only occur through release of the aerosol phaseparticulate matter, the mass of particulate matter may be equated withthe mass lost from the device or component during the delivery of theaerosol. In this case, the rate of aerosol formation is equal to thedecrease in mass of the device or component during the delivery eventdivided by the duration of the delivery event.

[0116] Rate of drug aerosol formation is determined, for example, bydelivering a chlordiazepoxide, betahistine, clonidine, testosterone,conjugated estrogens, estrogen esters, estradiol, estradiol esters,ethinyl estradiol, ethinyl estradiol esters, or hyoscyamine containingaerosol into a confined chamber via an inhalation device over a setperiod of time (e.g., 3 s). Where the aerosol is pure chlordiazepoxide,betahistine, clonidine, testosterone, conjugated estrogens, estrogenesters, estradiol, estradiol esters, ethinyl estradiol, ethinylestradiol esters, or hyoscyamine, the amount of drug collected in thechamber is measured as described above. The rate of drug aerosolformation is equal to the amount of chlordiazepoxide, betahistine,clonidine, testosterone, conjugated estrogens, estrogen esters,estradiol, estradiol esters, ethinyl estradiol, ethinyl estradiolesters, or hyoscyamine collected in the chamber divided by the durationof the collection time. Where the chlordiazepoxide, betahistine,clonidine, testosterone, conjugated estrogens, estrogen esters,estradiol, estradiol esters, ethinyl estradiol, ethinyl estradiolesters, or hyoscyamine containing aerosol comprises a pharmaceuticallyacceptable excipient, multiplying the rate of aerosol formation by thepercentage of chlordiazepoxide, betahistine, clonidine, testosterone,conjugated estrogens, estrogen esters, estradiol, estradiol esters,ethinyl estradiol, ethinyl estradiol esters, or hyoscyamine in theaerosol provides the rate of drug aerosol formation.

[0117] Utility of Physiologically Active Compound Containing Aerosols

[0118] Chlordiazepoxide containing aerosols are typically used for thetreatment of anxiety. Betahistine containing aerosols are typically usedfor the treatment of vertigo (Meniere's disease). Clonidine containingaerosols are typically used for the treatment of alcohol withdrawal,nicotine withdrawal, sedation, or hot flashes. Testosterone containingaerosols are typically used for testosterone replacement therapy.Conjugated estrogens and estrogen ester containing aerosols aretypically used for hormone replacement therapy (menopause). Estradiol,estradiol ester, ethinyl estradiol, and ethinyl estradiol estercontaining aerosols are typically used for hormone replacement therapy(estradiol and esters) and the prevention of pregnancy (ethinylestradiol and esters). Hyoscyamine containing aerosols are typicallyused for the treatment of peptic ulcers.

[0119] The following examples are meant to illustrate, rather thanlimit, the present invention.

[0120] Chlordiazepoxide hydrochloride, betahistine dihydrochloride,clonidine hydrochloride, testosterone, estradiol, certain estradiolesters, and hyoscyamine are commercially available from Sigma(www.sigma-aldrich.com). Obtaining a free base from a salt oresterifying an alcohol are done according to standard methods in theart. Compounds such as ethinyl estradiol are isolated from commerciallyavailable pharmaceutical preparations or synthesized using standardmethods in the art.

EXAMPLE 1 General Procedure for Volatilizing Compounds

[0121] A solution of drug in approximately 120 μL dichloromethane iscoated on a 3 cm×8 cm piece of aluminum foil. The dichloromethane isallowed to evaporate. The coated foil is wrapped around a 300 watthalogen tube (Feit Electric Company, Pico Rivera, Calif.), which isinserted into a glass tube sealed at one end with a rubber stopper.Running 60 V (45 V for chlordiazepoxide) of alternating current (drivenby line power controlled by a variac) through the bulb for 5 to 15 saffords thermal vapor (including aerosol), which is collected on theglass tube walls. Reverse-phase HPLC analysis with detection byabsorption of 225 nm light is used to determine the purity of theaerosol. (When desired, the system is flushed through with argon priorto volatilization.)

[0122] The following aerosol purities were obtained using this method:chlordiazepoxide (99% purity, 1.3 mg); estradiol-17-acetate (98.6%purity, 0.59 mg); estradiol-3,17-diacetate (96.9% purity, 1.07 mg);testosterone (100% purity, 0.93 mg); and, hyoscyamine (95.9% purity,1.07 mg).

[0123] To obtain higher purity aerosols, one can coat a lesser amount ofdrug, yielding a thinner film to heat. A linear decrease in filmthickness is associated with a linear decrease in impurities.

1. A composition for delivery of chlordiazepoxide consisting of acondensation aerosol a. formed by volatilizing a coating ofchlordiazepoxide on a solid support, having the surface texture of ametal foil, to a temperature sufficient to produce a heated vapor ofchlordiazepoxide and condensing the heated vapor of chlordiazepoxide toform condensation aerosol particles, b. wherein said condensationaerosol particles are characterized by less than 5% chlordiazepoxidedegradation products, and c. the condensation aerosol has an MMAD ofless than 3 microns.
 2. The composition according to claim 1, whereinthe aerosol particles are formed at a rate of at least 10⁹ particles persecond.
 3. The composition according to claim 2, wherein the aerosolparticles are formed at a rate of at least 10¹⁰ particles per second. 4.A composition for delivery of betahistine consisting of a condensationaerosol a. formed by volatilizing a coating of betahistine on a solidsupport, having the surface texture of a metal foil, to a temperaturesufficient to produce a heated vapor of betahistine and condensing theheated vapor of betahistine to form condensation aerosol particles, b.wherein said condensation aerosol particles are characterized by lessthan 5% betahistine degradation products, and c. the condensationaerosol has an MMAD of less than 3 microns.
 5. The composition accordingto claim 4, wherein the aerosol particles are formed at a rate of atleast 10⁹ particles per second.
 6. The composition according to claim 5,wherein the aerosol particles are formed at a rate of at least 10¹⁰particles per second.
 7. A composition for delivery of clonidineconsisting of a condensation aerosol a. formed by volatilizing a coatingof clonidine on a solid support, having the surface texture of a metalfoil, to a temperature sufficient to produce a heated vapor of clonidineand condensing the heated vapor of clonidine to form condensationaerosol particles, b. wherein said condensation aerosol particles arecharacterized by less than 5% clonidine degradation products, and c. thecondensation aerosol has an MMAD of less than 3 microns.
 8. Thecomposition according to claim 7, wherein the aerosol particles areformed at a rate of at least 10⁹ particles per second.
 9. Thecomposition according to claim 8, wherein the aerosol particles areformed at a rate of at least 10¹⁰ particles per second.
 10. Acomposition for delivery of testosterone consisting of a condensationaerosol a. formed by volatilizing a coating of testosterone on a solidsupport, having the surface texture of a metal foil, to a temperaturesufficient to produce a heated vapor of testosterone and condensing theheated vapor of testosterone to form condensation aerosol particles, b.wherein said condensation aerosol particles are characterized by lessthan 5% testosterone degradation products, and c. the condensationaerosol has an MMAD of less than 3 microns.
 11. The compositionaccording to claim 10, wherein the aerosol particles are formed at arate of at least 10⁹ particles per second.
 12. The composition accordingto claim 11, wherein the aerosol particles are formed at a rate of atleast 10¹⁰ particles per second.
 13. A composition for delivery ofconjugated estrogens consisting of a condensation aerosol a. formed byvolatilizing a coating of a conjugated estrogen on a solid support,having the surface texture of a metal foil, to a temperature sufficientto produce a heated vapor of the conjugated estrogen and condensing theheated vapor of the conjugated estrogen to form condensation aerosolparticles, b. wherein said condensation aerosol particles arecharacterized by less than 5% conjugated estrogen degradation products,and c. the condensation aerosol has an MMAD of less than 3 microns. 14.The composition according to claim 13, wherein the aerosol particles areformed at a rate of at least 10⁹ particles per second.
 15. Thecomposition according to claim 14, wherein the aerosol particles areformed at a rate of at least 10¹⁰ particles per second.
 16. Acomposition for delivery of estrogen esters consisting of a condensationaerosol a. formed by volatilizing a coating of estrogen esters on asolid support, having the surface texture of a metal foil, to atemperature sufficient to produce a heated vapor of the estrogen esterand condensing the heated vapor of the estrogen ester to formcondensation aerosol particles, b. wherein said condensation aerosolparticles are characterized by less than 5% estrogen ester degradationproducts, and c. the condensation aerosol has an MMAD of less than 3microns.
 17. The composition according to claim 16, wherein the aerosolparticles are formed at a rate of at least 10⁹ particles per second. 18.The composition according to claim 17, wherein the aerosol particles areformed at a rate of at least 10¹⁰ particles per second.
 19. Acomposition for delivery of estradiol consisting of a condensationaerosol a. formed by volatilizing a coating of estradiol on a solidsupport, having the surface texture of a metal foil, to a temperaturesufficient to produce a heated vapor of estradiol and condensing theheated vapor of estradiol to form condensation aerosol particles, b.wherein said condensation aerosol particles are characterized by lessthan 5% estradiol degradation products, and c. the condensation aerosolhas an MMAD of less than 3 microns.
 20. The composition according toclaim 19, wherein the aerosol particles are formed at a rate of at least10⁹ particles per second.
 21. The composition according to claim 20,wherein the aerosol particles are formed at a rate of at least 10¹⁰particles per second.
 22. A composition for delivery of estradiol estersconsisting of a condensation aerosol a. formed by volatilizing a coatingof an estradiol ester on a solid support, having the surface texture ofa metal foil, to a temperature sufficient to produce a heated vapor ofthe estradiol ester and condensing the heated vapor of the estradiolester to form condensation aerosol particles, b. wherein saidcondensation aerosol particles are characterized by less than 5%estradiol ester degradation products, and c. the condensation aerosolhas an MMAD of less than 3 microns.
 23. The composition according toclaim 22, wherein the aerosol particles are formed at a rate of at least10⁹ particles per second.
 24. The composition according to claim 23,wherein the aerosol particles are formed at a rate of at least 10¹⁰particles per second.
 25. A composition for delivery of ethinylestradiol consisting of a condensation aerosol a. formed by volatilizinga coating of ethinyl estradiol on a solid support, having the surfacetexture of a metal foil, to a temperature sufficient to produce a heatedvapor of ethinyl estradiol and condensing the heated vapor of ethinylestradiol to form condensation aerosol particles, b. wherein saidcondensation aerosol particles are characterized by less than 5% ethinylestradiol degradation products, and c. the condensation aerosol has anMMAD of less than 3 microns.
 26. The composition according to claim 25,wherein the aerosol particles are formed at a rate of at least 10⁹particles per second.
 27. The composition according to claim 26, whereinthe aerosol particles are formed at a rate of at least 10¹⁰ particlesper second.
 28. A composition for delivery of ethinyl estradiol estersconsisting of a condensation aerosol a. formed by volatilizing a coatingof an ethinyl estradiol ester on a solid support, having the surfacetexture of a metal foil, to a temperature sufficient to produce a heatedvapor of the ethinyl estradiol ester and condensing the heated vapor ofthe ethinyl estradiol ester to form condensation aerosol particles, b.wherein said condensation aerosol particles are characterized by lessthan 5% ethinyl estradiol ester degradation products, and c. thecondensation aerosol has an MMAD of less than 3 microns.
 29. Thecomposition according to claim 28, wherein the aerosol particles areformed at a rate of at least 10⁹ particles per second.
 30. Thecomposition according to claim 29, wherein the aerosol particles areformed at a rate of at least 10¹⁰ particles per second.
 31. Acomposition for delivery of hyoscyamine consisting of a condensationaerosol a. formed by volatilizing a coating of hyoscyamine on a solidsupport, having the surface texture of a metal foil, to a temperaturesufficient to produce a heated vapor of hyoscyamine and condensing theheated vapor of hyoscyamine to form condensation aerosol particles, b.wherein said condensation aerosol particles are characterized by lessthan 5% hyoscyamine degradation products, and c. the condensationaerosol has an MMAD of less than 3 microns.
 32. The compositionaccording to claim 31, wherein the aerosol particles are formed at arate of at least 10⁹ particles per second.
 33. The composition accordingto claim 32 wherein the aerosol particles are formed at a rate of atleast 10¹⁰ particles per second.
 34. A method of producingchlordiazepoxide in an aerosol form comprising: a. heating a coating ofchlordiazepoxide on a solid support, having the surface texture of ametal foil, to a temperature sufficient to volatilize thechlordiazepoxide to form a heated vapor of the chlordiazepoxide, and b.during said heating, passing air through the heated vapor to produceaerosol particles of the chlordiazepoxide comprising less than 5%chlordiazepoxide degradation products, and an aerosol having an MMAD ofless than 3 microns.
 35. The method according to claim 34, wherein theaerosol particles are formed at a rate of greater than 10⁹ particles persecond.
 36. The method according to claim 35, wherein the aerosolparticles are formed at a rate of greater than 10¹⁰ particles persecond.
 37. A method of producing betahistine in an aerosol formcomprising: a. heating a coating of betahistine on a solid support,having the surface texture of a metal foil, to a temperature sufficientto volatilize the betahistine to form a heated vapor of the betahistine,and b. during said heating, passing air through the heated vapor toproduce aerosol particles of the betahistine comprising less than 5%betahistine degradation products, and an aerosol having an MMAD of lessthan 3 microns.
 38. The method according to claim 37, wherein theaerosol particles are formed at a rate of greater than 10⁹ particles persecond.
 39. The method according to claim 38, wherein the aerosolparticles are formed at a rate of greater than 10¹⁰ particles persecond.
 40. A method of producing clonidine in an aerosol formcomprising: a. heating a coating of clonidine on a solid support, havingthe surface texture of a metal foil, to a temperature sufficient tovolatilize the clonidine to form a heated vapor of the clonidine, and b.during said heating, passing air through the heated vapor to produceaerosol particles of the clonidine comprising less than 5% clonidinedegradation products, and an aerosol having an MMAD of less than 3microns.
 41. The method according to claim 40, wherein the aerosolparticles are formed at a rate of greater than 10⁹ particles per second.42. The method according to claim 41, wherein the aerosol particles areformed at a rate of greater than 10¹⁰ particles per second.
 43. A methodof producing testosterone in an aerosol form comprising: a. heating acoating of testosterone on a solid support, having the surface textureof a metal foil, to a temperature sufficient to volatilize thetestosterone to form a heated vapor of the testosterone, and b. duringsaid heating, passing air through the heated vapor to produce aerosolparticles of the testosterone comprising less than 5% testosteronedegradation products, and an aerosol having an MMAD of less than 3microns.
 44. The method according to claim 43, wherein the aerosolparticles are formed at a rate of greater than 10⁹ particles per second.45. The method according to claim 44, wherein the aerosol particles areformed at a rate of greater than 10¹⁰ particles per second.
 46. A methodof producing conjugated estrogens in an aerosol form comprising: a.heating a coating of a conjugated estrogen on a solid support, havingthe surface texture of a metal foil, to a temperature sufficient tovolatilize the conjugated estrogen to form a heated vapor of theconjugated estrogen, and b. during said heating, passing air through theheated vapor to produce aerosol particles of the conjugated estrogencomprising less than 5% conjugated estrogen degradation products, and anaerosol having an MMAD of less than 3 microns.
 47. The method accordingto claim 46, wherein the aerosol particles are formed at a rate ofgreater than 10⁹ particles per second.
 48. The method according to claim47, wherein the aerosol particles are formed at a rate of greater than10¹⁰ particles per second.
 49. A method of producing estrogen esters inan aerosol form comprising: a. heating a coating of an estrogen ester ona solid support, having the surface texture of a metal foil, to atemperature sufficient to volatilize the estrogen ester to form a heatedvapor of the estrogen esters, and b. during said heating, passing airthrough the heated vapor to produce aerosol particles of the estrogenester comprising less than 5% estrogen ester degradation products, andan aerosol having an MMAD of less than 3 microns.
 50. The methodaccording to claim 49, wherein the aerosol particles are formed at arate of greater than 10⁹ particles per second.
 51. The method accordingto claim 50, wherein the aerosol particles are formed at a rate ofgreater than 10¹⁰ particles per second.
 52. A method of producingestradiol in an aerosol form comprising: a. heating a coating ofestradiol on a solid support, having the surface texture of a metalfoil, to a temperature sufficient to volatilize the estradiol to form aheated vapor of the estradiol, and b. during said heating, passing airthrough the heated vapor to produce aerosol particles of the estradiolcomprising less than 5% estradiol degradation products, and an aerosolhaving an MMAD of less than 3 microns.
 53. The method according to claim52, wherein the aerosol particles are formed at a rate of greater than10⁹ particles per second.
 54. The method according to claim 53, whereinthe aerosol particles are formed at a rate of greater than 10¹⁰particles per second.
 55. A method of producing estradiol esters in anaerosol form comprising: a. heating a coating of an estradiol ester on asolid support, having the surface texture of a metal foil, to atemperature sufficient to volatilize the estradiol ester to form aheated vapor of the estradiol ester, and b. during said heating, passingair through the heated vapor to produce aerosol particles of theestradiol ester comprising less than 5% estradiol ester degradationproducts, and an aerosol having an MMAD of less than 3 microns.
 56. Themethod according to claim 55, wherein the aerosol particles are formedat a rate of greater than 10⁹ particles per second.
 57. The methodaccording to claim 56, wherein the aerosol particles are formed at arate of greater than 10¹⁰ particles per second. 58 A method of producingethinyl estradiol in an aerosol form comprising: a. heating a coating ofethinyl estradiol on a solid support, having the surface texture of ametal foil, to a temperature sufficient to volatilize the ethinylestradiol to form a heated vapor of the ethinyl estradiol, and b. duringsaid heating, passing air through the heated vapor to produce aerosolparticles of the ethinyl estradiol comprising less than 5% ethinylestradiol degradation products, and an aerosol having an MMAD of lessthan 3 microns.
 59. The method according to claim 59, wherein theaerosol particles are formed at a rate of greater than 10⁹ particles persecond.
 60. The method according to claim 60, wherein the aerosolparticles are formed at a rate of greater than 10¹⁰ particles persecond.
 61. A method of producing ethinyl estradiol esters in an aerosolform comprising: a. heating a coating of an ethinyl estradiol ester on asolid support, having the surface texture of a metal foil, to atemperature sufficient to volatilize the ethinyl estradiol ester to forma heated vapor of the ethinyl estradiol ester, and b. during saidheating, passing air through the heated vapor to produce aerosolparticles of the ethinyl estradiol ester comprising less than 5% ethinylestradiol ester degradation products, and an aerosol having an MMAD ofless than 3 microns.
 62. The method according to claim 61, wherein theaerosol particles are formed at a rate of greater than 10⁹ particles persecond.
 63. The method according to claim 62, wherein the aerosolparticles are formed at a rate of greater than 10¹⁰ particles persecond.
 64. A method of producing hyoscyamine in an aerosol formcomprising: a. heating a coating of hyoscyamine on a solid support,having the surface texture of a metal foil, to a temperature sufficientto volatilize the hyoscyamine to form a heated vapor of the hyoscyamine,and b. during said heating, passing air through the heated vapor toproduce aerosol particles of the hyoscyamine comprising less than 5%hyoscyamine degradation products, and an aerosol having an MMAD of lessthan 3 microns.
 65. The method according to claim 65, wherein theaerosol particles are formed at a rate of greater than 10⁹ particles persecond.
 66. The method according to claim 65, wherein the aerosolparticles are formed at a rate of greater than 10¹⁰ particles persecond.